Mitochondrial substrate utilization regulates cardiomyocyte cell-cycle progression
Mitochondrial substrate utilization regulates cardiomyocyte cell-cycle progression
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DOI：
10.1038/s42255-020-0169-x
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发表时间：
2020-02-01
影响因子：
20.8
通讯作者：
Sadek, Hesham A.
中科院分区：
文献类型：
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作者：
Cardoso, Alisson C.;Lam, Nicholas T.;Sadek, Hesham A.
新生哺乳动物的心脏能够在出生后的一段短暂时间内再生。然而，这种再生能力在出生后的第一周内就会丧失，这与出生后从无氧糖酵解转变为线粒体氧化磷酸化，特别是向脂肪酸利用转变是一致的。尽管脂肪酸β氧化具有能量优势，但当利用脂肪酸时，心肌线粒体产生更高的活性氧物种，这被认为通过诱导DNA损伤和激活DNA损伤反应(DDR)途径而在心肌细胞周期停滞中发挥作用。在这里，我们发现抑制脂肪酸的利用促进了出生后心脏的心肌细胞增殖。首先，喂养缺乏脂肪酸的牛奶的新生小鼠表现出出生后心肌细胞增殖窗口的延长；然而，细胞周期最终停止。接下来，我们建立了他莫昔芬诱导的心肌细胞特异性丙酮酸脱氢酶激酶4(PDK4)基因敲除的小鼠模型，以选择性地增强心肌细胞中糖酵解衍生的丙酮酸的氧化。条件性PDK4缺失导致丙酮酸脱氢酶活性增加，从而导致葡萄糖相对于脂肪酸氧化的增加。PDK4缺失还导致心肌细胞体积缩小，DNA损伤减轻，DDR标志物表达减少，心肌细胞增殖增加。心肌梗死后，PDK4的可诱导缺失改善了左心功能，减少了重构。总的来说，抑制心肌细胞中脂肪酸的利用促进了细胞的增殖，并可能成为心脏再生治疗的一个可行的靶点。
The neonatal mammalian heart is capable of regeneration for a brief window of time after birth. However, this regenerative capacity is lost within the first week of life, which coincides with a postnatal shift from anaerobic glycolysis to mitochondrial oxidative phosphorylation, particularly towards fatty-acid utilization. Despite the energy advantage of fatty-acid beta-oxidation, cardiac mitochondria produce elevated rates of reactive oxygen species when utilizing fatty acids, which is thought to play a role in cardiomyocyte cell-cycle arrest through induction of DNA damage and activation of DNA-damage response (DDR) pathway. Here we show that inhibiting fatty-acid utilization promotes cardiomyocyte proliferation in the postnatal heart. First, neonatal mice fed fatty-acid-deficient milk showed prolongation of the postnatal cardiomyocyte proliferative window; however, cell-cycle arrest eventually ensued. Next, we generated a tamoxifen-inducible cardiomyocyte-specific pyruvate dehydrogenase kinase 4 (PDK4) knockout mouse model to selectively enhance oxidation of glycolytically derived pyruvate in cardiomyocytes. Conditional PDK4 deletion resulted in an increase in pyruvate dehydrogenase activity and consequently an increase in glucose relative to fatty-acid oxidation. Loss of PDK4 also resulted in decreased cardiomyocyte size, decreased DNA damage and expression of DDR markers and an increase in cardiomyocyte proliferation. Following myocardial infarction, inducible deletion of PDK4 improved left ventricular function and decreased remodelling. Collectively, inhibition of fatty-acid utilization in cardiomyocytes promotes proliferation, and may be a viable target for cardiac regenerative therapies.